Use of tachykinin antagonists in the treatment of emesis

Abstract: The present invention relates to the use of certain tachykinin antagonists, including substance P antagonists and other neurokinin antagonists, in the treatment of emesis.

Description: The present invention relates to the use of certain NK 1 receptor antagonists, in the treatment of emesis. Tachykinin antagonists, including substance P antagonists, are known to be useful in the treatment of a variety of disorders including pain, inflammatory diseases, allergic disorders, CNS disorders, skin disorders, cough and gastrointestinal disorders such as ulcerative colitis and Crohn's disease. It has now been found that NK 1 receptor antagonists are useful in the treatment of emesis. Our co-pending European Patent Application No. 92202831 (Publication No. 0533280) relates to the use of tachykinin antagonists, including NK 1 receptor antagonists, in the treatment of emesis. The use of the NK 1 receptor antagonists specifically disclosed in co-pending European Patent Application No. 92202831 in the treatment of emesis is not included within the scope of the present invention. The invention accordingly provides, in a first aspect, the novel use of the NK 1 receptor antagonists, generically and specifically disclosed in published PCT Patent Application No. 92/21677, in the treatment of emesis. There is also provided as a further aspect of the invention the use of the NK 1 receptor antagonists, generically and specifically disclosed in the above referenced patent specification, for the preparation of a medicament for the treatment of emesis. It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms. NK 1 receptor antagonists, disclosed in the above referenced patent specification, have been shown to have anti-emetic activity as indicated by for example their ability to inhibit cisplatin- or radiation-induced emesis in the ferret. The treatment of emesis mentioned hereinbefore includes the treatment of nausea, retching and vomiting. Emesis includes acute emesis, delayed emesis and anticipatory emesis. NK 1 receptor antagonists are useful in the treatment of emesis however induced. For example, emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; antimetabolites, e.g. cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation therapy, e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g. gastritis; pregnancy; vestibular disorders, such as motion sickness and vertigo; post-operative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g. altitude sickness); and opioid analgesics, such as morphine. Accordingly, the NK 1 receptor antagonists for use in the present invention include those generically and specifically disclosed in:- WO 92/21677, i.e. compounds of the formula wherein R 1 is methoxy and R 2 is independently selected from the group consisting of isopropyl, tert-butyl, methyl, ethyl and sec-butyl; and the pharmaceutically acceptable salts of such compounds. The NK 1 receptor antagonists may be administered as the raw chemical but the active ingredients are preferably presented as a pharmaceutical formulation. Suitable pharmaceutical formulations are described in the above referenced patent specification. Thus, the NK 1 receptor antagonists may be formulated for oral, buccal, parenteral, depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose). Oral and parenteral formulations are preferred. For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl- p -hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound. For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner. The NK 1 receptor antagonists may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The NK 1 receptor antagonists may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. The NK 1 receptor antagonists may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. For intranasal administration, the NK 1 receptor antagonists may be formulated as solutions for administration via a suitable metered or unit dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device. Suitable dose ranges are also described in the above referenced patent specification, that is to say that for use as anti-emetics the compounds may be used at doses appropriate for other conditions for which NK 1 receptor antagonists are known to be useful. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient, and the precise dosage will be ultimately at the discretion of the attendant physician or veterinarian. The dosage will also depend on the route of administration and the particular compound selected. A suitable dose range is for example 0.1mg/kg to about 400mg/kg bodyweight per day. The NK 1 receptor antagonists may, if desired, be administered in combination with one or more other therapeutic agents and formulated for administration by any convenient route in a conventional manner. Appropriate doses will be readily appreciated by those skilled in the art. For example, the NK 1 receptor antagonists may be administered in combination with a systemic antiinflammatory corticosteroid such as methyl prednisolone or dexamethasone, or a 5HT 3 antagonist such as ondansetron, granisetron or metoclopramide. Biological Data The anti-emetic activity of the compounds defined hereinbefore is demonstrated by their ability to inhibit cisplatin- or radiation-induced emesis in the ferret. Cisplatin Test In this model of emesis the onset of retching and vomiting occurs approximately 1 hour after the administration of cisplatin (200mg/m 2 i.p.). At first retch in response to cisplatin, the compound is administered (e.g. i.p., p.o., i.v., s.c., i.c.v.) and its effect on emesis determined by comparison with appropriate controls (e.g. water). Radiation Test In this model of emesis the onset of retching and vomiting occurs approximately 20 minutes after whole body irradiation (2 Grey = 200 Rads). The compound is administered (e.g. i.p., p.o., i.v., s.c.) immediately after irradiation and its effect on emesis determined by comparison with appropriate controls. Reference Example The compound (2S,3S)-3-(2-methoxybenzylamino)-2-phenyl piperidine inhibited cisplatin-induced emesis in the ferret when administered at a dose of 3mg/kg i.p. The (2R, 3R) enantiomer of the above compound, which is 1000- fold less active as an NK 1 receptor antagonist than the (2S,3S) enantiomer, was inactive in the cisplatin emesis test at the same dose.

Claims: The use of an NK 1 receptor antagonist selected from compounds of the formula (M) wherein R 1 is methoxy and R 2 is independently selected from methyl, ethyl isopropyl, sec-butyl or t-butyl and the pharmaceutically acceptable salts of such compounds for the preparation of a medicament for the treatment of emesis. The use according to Claim 1 wherein R 1 is methoxy and R 2 is methyl. The use according to Claim 1 wherein R 1 is methoxy and R 2 is ethyl. The use according to Claim 1 wherein R 1 is methoxy and R 2 is isopropyl. The use according to Claim 1 wherein R 1 is methoxy and R 2 is sec-butyl. The use according to Claim 1 wherein R 1 is methoxy and R 2 is t-butyl. The use according to any one of Claims 1-6 wherein said emesis is induced by cancer chemotherapeutic agents, radiation sickness, radiation therapy, poisons, toxins, pregnancy, vestibular disorders, post-operative sickness, gastrointestinal obstruction, reduced gastrointestinal motility, visceral pain, migraine, increased intercranial pressure, decreased intercranial pressure, or opioid analgesics. The use according to Claim 7 wherein said emesis is induced by a cancer chemotherapeutic agent, radiation sickness or radiation therapy. The use according to Claim 8 wherein said cancer chemotherapeutic agent is selected from cyclophosphamide, carmustine, lomustine, chloroambucil, dactinomycin, doxorubicin, mitomycin-C, bleomycin, cytarabine, methotrexate, 5-fluorouracil, etoposide, vinblastine, vincristine, cisplatin, dacarbazine, procarbazine, hydroxyurea, and combinations thereof. The use according to Claim 9 wherein said emesis is induced by cisplatin or cyclophosphamide.

Inventors: BUNCE KEITH THOMAS, HAGAN RUSSELL MICHAEL, BUNCE, KEITH THOMAS, HAGAN, RUSSELL MICHAEL
Applicants: GLAXO GROUP LTD, GLAXO GROUP LIMITED
Application year: 1994
Main classification: A61K31
IPC codes: A61K31, C07D211, C07D275, C07D209, C07D227, A61K38, C07D215, A61P43, C07D471, A61P1, A61K33, C07D311, C07D453, C07D207, C07D487